DESCRIPTION (Applicant's abstract): The main objective of this FIRST Award is to establish the Principal Investigator, Dr. Krystal, as an independent clinical researcher in neuropsychiatry. The research focus is the evaluation of electroconvulsive therapy (ECT) clinical stimulus dosing strategies to improve the tradeoff between treatment efficacy and cognitive side effects. The proposed two-stage independent research program is designed to implement in the clinical setting an ictal electroencephalographic (EEG) algorithm for determining the therapeutic adequacy of individual ECT seizures and to determine whether dosing ECT treatments according to such an algorithm improves the tradeoff between the efficacyand safety of ECT. It also represents the first comparison of 150% and 300% supratheshold unilateral (UL) ECT art] thereby fills an important gap in present understanding of stimulus dosing independent of ictal EEG issues. Stage I of the proposed project overlaps with the final year of the PI's present Scientist Development Award in which he will develop an ictal EEG based seizure adequacy model. Stage II addresses the presently unresolved question of whether the clinical dosing of ECT on the basis of an ictal EEG adequacy model improves the efficacy and safety of UL ECT over present stimulus dosing strategies. This will be achieved by randomizing depressed subjects to one of 3 UL ECT stimulus dosing paradigms: I) EEG Algorithm Based Dosing (EEG-Stimulus dosing is determined on-line on the basis of the ictal EEG-based adequacy algorithm developed in Stage I in order to maintain the minimum effective stimulus dosage; 2) Lower Clinical Dosing (LCLIN)-Determination of the seizure threshold at treatment and administering subsequent treatments at an intensity that is 150% suprathreshold. 3) Higher Clinical Dosing (HCLIN) The same as LCLIN dosing except 300% above threshold. We will test the hypothesis that EEG and LCLIN will be more effective than LCLIN dosing, while EEG and LCLIN will have less side-effects than HCLIN dosing. Thus, we will test the hypothesis that EEG dosing will optimize the tradeoff between beneficial effects and side-effects compared with conventional titration-based dosing. Because an EEG-based dosing algorithm can become widely available to clinicians in ECT devices, the results of the proposed study will broadly optimize the clinical efficacy and safety of ECT.